DS0407 - Exploration du système nerveux dans son fonctionnement normal et pathologique

Knock in Mouse Models and The Pathophysiology of Microtubule associated Cortical Development Disorders – KI-Models-MCD

Submission summary

Epilepsy is a chronic neurological disorder that affects more than 50 million people globally, with 50% of patients developing their first seizure in childhood. In approximately 70% of cases the symptoms of epilepsy can be treated with anti-epileptic drugs (e.g. Benzodiazepines), but in the remaining 30% few treatment options are available. Drug-resistant epilepsy has devastating personal, social and economic consequences, which is reflected by the recent declaration from the World Health Organization that epilepsy is a major public health concern.
The origin of drug resistant epileptogenic disorders is heterogeneous, however some are related to the disruption of genetic factors/programs required for the coordinated timing of proliferation, migration and differentiation of neurons in development. These disorders include periventricular nodular heterotopia, lissencephaly/pachygyria (LIS spectrum), focal cortical dysplasia, and polymicrogyria. Individuals who suffer from these diseases often present with intellectual deficiency, frequently accompanied by epilepsy. Dominant mutations and deletions in doublecortin (DCX) and LIS1, proteins which are associated with the microtubule cytoskeleton, have both been found to cause lissencephaly. Autosomal recessive lissencephaly has been described in individuals with mutations in the reelin gene, and cerebellar hypoplasia with cerebral gyral simplification in individuals with mutations in the reelin receptor, VLDLR (very low density lipoprotein receptor).
We have previously shown that de novo mutations in the alpha tubulin TUBA1A, can cause cortical dysgenesis with microcephaly, cerebellar, hippocampal, corpus callosum, cortico-spinal tracts and brainstem abnormalities. Subsequent collaborative studies carried out between the two principal applicants has further implicated other tubulin genes (TUBB2B, TUBB3, TUBB5 and TUBG1) and MT-related proteins (KIF5C, KIF2A, DYNC1H1) in a large spectrum of malformations of cortical development (MCD) that includes microcephaly, polymicrogyria, and pachygyria. In the majority of cases affected individuals also present with drug resistant epilepsy. More recently, we showed that de novo mutations in microtubule associated serine/threonine kinase 1 (MAST1) are associated with a broad array of cortical malformations including polymicrgyria and pachygyria (confidential data). It is apparent from these studies that both the gene and the residue mutated are critical in determining the disease state, however, little is known about the underlying cellular and molecular mechanisms and to what degree they converge.
Our primary goal is to gain a better understanding of the molecular pathology that is associated with MCD related to tubulins and MT-related proteins. With this objective in mind we have undertaken complementary investigations in order to assess contributions of MT-dependent processes with respect to the pathogenesis of MCD. In addition to the ongoing and well advanced biochemical functional, extensive expression studies as well in vivo in utero electroporation based studies, we have generated a number of unique mouse models. In this project we propose to undertake an in depth characterisation of these mice which will contribute to a deeper understanding of the pathophysiology of MCDs, and may identify potential targets that could be exploited to modulate epilepsy severity.

Project coordination


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


IMP Research Institute of Molecular Pathology GmbH

Help of the ANR 204,048 euros
Beginning and duration of the scientific project: March 2016 - 36 Months

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